EP0262125B1 - AICA riboside zur prophylaktischen Behandlung von Krankheiten mit einer verminderten Durchblutung. - Google Patents

AICA riboside zur prophylaktischen Behandlung von Krankheiten mit einer verminderten Durchblutung. Download PDF

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Publication number
EP0262125B1
EP0262125B1 EP86902696A EP86902696A EP0262125B1 EP 0262125 B1 EP0262125 B1 EP 0262125B1 EP 86902696 A EP86902696 A EP 86902696A EP 86902696 A EP86902696 A EP 86902696A EP 0262125 B1 EP0262125 B1 EP 0262125B1
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Prior art keywords
adenosine
aica riboside
use according
blood flow
aica
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EP86902696A
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French (fr)
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EP0262125A4 (de
EP0262125A1 (de
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Harry Edward Gruber
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Sicor Inc
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Sicor Inc
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
    • C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
    • C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
    • C07H19/056—Triazole or tetrazole radicals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/08—Antiallergic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/08—Vasodilators for multiple indications
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
    • C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
    • C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
    • C07H19/052—Imidazole radicals

Definitions

  • This invention relates to the use of AICA riboside for the preparation of a medicament for the prophylactic treatment of diseases associated with undesired restricted blood flow, i.e. diseases that respond beneficially to increases in extracellular levels of adenosine.
  • Adenosine belongs to the class of biochemicals termed purine nucleosides and is a key biochemical cell regulatory molecule, as described by Fox and Kelly in the Annual Reviews of Biochemistry , Vol. 47, p. 635, 1978, that interacts with a wide variety of cell types, and is responsible for a myriad of biological effects.
  • adenosine is a potent vasodilator, inhibitor of immune cell function, activator of mast cell degranulation, an inhibitor of granulocyte activation, and a putative inhibitory neurotransmitter.
  • adenosine's broad spectrum of biological activity considerable effort has been, and continues to be aimed at establishing practical therapeutic uses for the molecule, and its analogs.
  • adenosine or similar purine nucleosides are thought to act at the level of the cell plasma membrane, by binding to receptors anchored in the membrane, past work has focused on increasing the extracellular levels of the molecules.
  • adenosine or its analogs are toxic at concentrations that have to be administered to a patient to maintain an efficacious extracellular therapeutic level, thus the administration of adenosine alone is of little therapeutic use. Consequently other ways of maintaining high local extracellular levels of adenosine have been sought.
  • the three most used are: a) interference with the uptake of adenosine with reagents that specifically block adenosine transport as described by Paterson et al., in the Annals of the New York Academy of Sciences , Vol. 255, p. 402, 1975; b) prevention of the metabolism of adenosine which, in turn, makes cellular adenosine available for extracellular transport and use outside the cell as described by Carson and Seegmiller in The Journal of Clinical Investigation , Vol. 57, p. 274, 1976; and c) the use of analogs of adenosine constructed to bind to adenosine cell plasma membrane receptors with lower dissociation constants than adenosine.
  • Methods of increasing the extracellular levels of adenosine by altering adenosine metabolism are primarily founded on the use of chemicals that inhibit enzymatic degradation of adenosine. Most of this work has focused on identifying inhibitors of adenosine deaminase which converts adenosine to inosine. Adenosine deaminase is inhibited by coformycin, 2'-deoxyco-formycin or erythro 9-(2-hydroxy-3-nonyl) adenine hydrochloride.
  • adenosine analogs have been generated that exhibit structural modifications to the purine ring, alterations in substituent groups attached to the purine ring, and modifications to, or alterations in the site of attachment of the carbohydrate moiety.
  • Halogenated adenosine derivatives appear to be most promising and, as described by Wolff et al. in the Journal of Biological Chemistry , Vol. 252, p. 681, 1977, exert biological effects similar to those caused by adenosine.
  • a novel method for alleviating disease based on increasing the extracellular concentration of adenosine, or adenosine analogs utilizing 5-amino-1-( ⁇ -D-ribofuranosyl) imidazole-4-carboxamide (AICA riboside).
  • AICA riboside 5-amino-1-( ⁇ -D-ribofuranosyl) imidazole-4-carboxamide
  • This compound is administered to a patient and is taken up and converted to mono and sometimes triphosphate by cells.
  • Adenosine or inosine are generated from adenosine triphosphate in the course of rapid cellular energy utilization such as during seizure activity or during decreased blood flow by a series or intracellular biochemical reactions.
  • the production of inosine is much greater than that of adenosine (approximately 100 to 1).
  • Nucleosides such as AICA riboside enhance the production of adenosine.
  • the increase in adenosine release is at least partly due to a reduction in 5'nucleotidase activity. It is apparent from the diagram below that with reduced 5'nucleotidase activity IMP is not cleaved as rapidly to inosine and more nucleotide is converted to AMP which builds up and is converted to adenosine.
  • the K M for AMP is approximately 10 fold higher than for IMP.
  • Diagram 1 Metabolism of adenosine. This diagram illustrates the pathways by which adenosine is formed and degraded within cells. Adenosine may also be transported into cells or released from cells.
  • the metabolism of 2'-deoxyadenosine may utilize some of these pathways: 1 , S-adenosylmethionine methyltransferases; 2 , S-adenosylhomocysteine hydrolase; 3 , adenoside deaminase; 4 , purine nucleoside phosphorylase; 5 & 6 , xanthine oxidase; 7 , transport mechanisms; 8 adenosine phosphorylase (not established); 9 , adenosine kinase; 10 5'nucleotidase and non-specific phosphatase; 11 , adenylate kinase; 12 , nucleoside diphosphokinase; 13 , adenylate cyclase.
  • AICA riboside affords a medically beneficial means of establishing a high local extracellular concentration of adenosine without the toxicity, or nonspecific uptake problems associated with other techniques that regulate extracellular adenosine levels.
  • FIG. 1 In vivo effect of 5-amino-(1- ⁇ -D-ribofuranosyl) imidazole-4-carboxamide (AICA riboside) on regional myocardial blood flow during coronary artery occlusion in dogs. Regional myocardial blood flow was measured using radiolabelled microspheres infused into the left atrium at 5 (open) and 60 (hatched) minutes of occlusion. The means plus the standard deviations are graphed.
  • AICA riboside 5-amino-(1- ⁇ -D-ribofuranosyl) imidazole-4-carboxamide
  • FIG. 3 The effect of AICA riboside treatment on coronary venous adenosine concentrations. Coronary venous blood was collected into equal volumes of chilled 2N perchloric acid at various times before and after coronary artery occlusion. Supernatant from these extracts were neutralized with alamine and freon and evaluated by high performance liquid chromotography. The mean adenosine concentrations +/- standard deviations for the 5 saline treated ( ⁇ ) and 6 AICA riboside treated ( ⁇ ) dogs are graphed.
  • AICA riboside The effect of AICA riboside on agenosine transport can be demonstrated either in vitro or in vivo where the effective concentration of either molecule is 10 ⁇ M-100 ⁇ M.
  • AICA riboside When delivered to cells in vitro AICA riboside can be dissolved in aqueous solution and added directly to the culture media.
  • AICA riboside To deliver AICA riboside to patients, it is anticipated that the same may be administered orally since it is not readily degraded by enzymes in the body, or by exposure to low pH presence in the stomach. There is no a priori reason for believing that the drug cannot also be administered intravenously, or by direct intramuscular injection, topically, or by inhalation.
  • AICA riboside Upon contact with activated energy-requiring target cells, AICA riboside is transported intracellularly by a plasma-membrane bound facilitated diffusion transport system where it can be phosphorylated by adenosine kinase to yield nucleotide monophosphate.
  • the latter chemical can be converted to the triphosphate, and is an intermediate in the de novo synthesis of purine nucleotides.
  • the amount of adenosine remaining in the cells is analyzed by high pressure liquid column chromatography after isolation from the cells as described by Matsumoto et al., in The Journal of Biological Chemistry , Vol. 254, p. 8956, 1979.
  • the amount of extracellular adenosine can be regulated by increasing or decreasing the concentration of the AICA riboside present in the cellular growth environment, if the adenosine level is too low to be medically beneficial, it can be increased by increasing the amount of AICA riboside administered. Similarly, if the amount of adenosine is too great, it can be reduced by reducing the amount of AICA riboside.
  • AICA riboside treatment will benefit patients suffering from a variety of illnesses.
  • AICA riboside it should be possible to use AICA riboside to treat diseases that arise from, or are aggravated by, insufficient blood flow through a particular organ. For example, angina pectoris, transient ischemic attacks, or migraine headaches can be treated by administering AICA riboside. This is expected since adenosine is known to be a potent vasodilator acting by reducing vascular smooth muscle contraction.
  • AICA riboside In addition to acting as a vasodilator, AICA riboside increases collateral blood flow by a second mechanism. Often granulocytes stick to microvasculature in the region of restricted blood flow. AICA riboside causes granulocytes to dislodge, and in doing so help to reestablish normal blood flow. Thus, the uptake of AICA riboside by smooth muscle cells followed by subsequent release of adenosine should cause vasodilation and/or removal of granulocytes.
  • Another disease associated with restricted blood flow is myocardial arrhythmia. Although restricted blood flow initiates the onset of arrhythmia, the precise cause is unknown. However, it is known that lipid peroxidation by oxygen radicals is arrhythmogenic. Since the latter are secreted by granulocytes, AICA riboside inhibition of granulocyte activation can be expected to control arrhythmia. In addition, granulocytes are in higher concentration in areas of arteriosclerosis. Suppression of their activation might reduce the release of other mediators of arrhythmias.
  • Figures 2 and 3 show the results of a series of experiments carried out to demonstrate the effects of AICA ribosides on adenosine levels in blood, and to correlate the increase in adenosine with increased blood flow.
  • Thirteen mongrel dogs were anesthetized with phenobarbital.
  • the anterior coronary vein was cannulated and a blood sample was collected into 2N perchloric acid.
  • Saline or 100mM AICA riboside in saline was randomly selected for infusion into the femoral vein for 45 minutes prior to coronary artery occlusion at a rate of 1 ml/min.
  • Coronary venous blood was collected and assayed for adenosine as described in Example 1 5 minutes prior to occlusion, and after 1, 10, 20, 30 and 50 minutes of occlusion of the left anterior descending coronary artery as well as 1 minute after reperfusion.
  • Regional myocardial blood flow was measured with 15 ⁇ m radiolabelled spheres infused into the left atrium at 5 and 60 minutes during the ischemic period as described by Heymann et al. in Prog. C.V. Dis. 20, 55 (1977). The electrocardiogram and arterial pressure were monitored throughout the period of ischemia.
  • Six AICA riboside treated and five saline treated dogs survived the procedure. Two of the surviving saline treated animals fibrillated.
  • the concentration of AICA riboside in AICA riboside treated dogs immediately before occlusion was 57.4 +/- 40.2 ⁇ M. The range was 4.4 to 100 ⁇ M.
  • Figure 2 shows that adenosine levels are dramatically increased upon AICA riboside perfusion
  • Figure 3 shows that regional myocardial blood flow to the ischemic myocardium was significantly greater in AICA riboside than in saline treated animals.
  • a similar degree of difference in flow was seen in endocardium and epicardium, and there were no changes between 5 and 60 minutes of ischemia.
  • AICA riboside did not alter flow to normal myocardium, as the non-ischemic tissue flow rates are remarkably similar between the two groups.
  • Systemic arterial pressure and heart rate at 5 and 60 minutes showed no significant differences between the two groups of dogs. Arterial blood gas-content and systemic venous granulocyte counts were not significantly different between the two groups.
  • AICA riboside enhances collateral coronary flow to ischemic myocardium possibly by augmenting adenosine release and thus vasodilating and/or inhibiting granulocyte capillary plugging.
  • AICA riboside for treating heart disease, a dog model of angina was developed. This consists of partially obstructing by placing a ring about the proximate portion of the coronary arteries feeding the dog myocardium. The ring slowly absorbs fluid and further constricts the artery over several weeks. Consequently when the dogs are exercised, they display the classical electrocardiogram and wall tension changes associated with angina. These dogs were treated with drugs known to relieve angina in humans, such as Nifedipine, and were shown to be of no help. However, when the same dogs were subsequently treated with AICA riboside, there was a dramatic, approximately 30%, increase in blood flow through the coronary arteries as measured by doppler readings. Moreover, there was also at least a two-fold increase in myocardium contractility in the ischemic region as measured by wall thickness.
  • AICA riboside treatment on coronary infarct size was determined in rats by inducing restricted blood flow by tying off the coronary artery and subsequently dosing the animals with either AICA riboside in saline, or saline or alone. Further, the animals were continuously exposed by infusion of either AICA riboside or a saline using osmotic mini-pumps well-known to those in the art. After three weeks the rats were sacrificed and infarct size quantitated by planinarizing stained sections of fixed hearts. The results showed that in AICA riboside treated rats there is a reduction of infarct size of approximately 24% compared to saline-treated controls.

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Claims (14)

  1. Verwendung von AICA-Ribosid zur Herstellung eines Arzneimittels für die prophylaktische Behandlung von Krankheiten, die mit unerwünschtem verminderten Blutfluß einhergehen.
  2. Verwendung nach Anspruch 1, worin das AICA-Ribosid so formuliert wird, daß nach Verabreichung die Blutkonzentration von AICA-Ribosid im Bereich von 4,4 bis 100 µM liegt.
  3. Verwendung nach Anspruch 1 zur lokalen Erhöhung der Adenosinkonzentrationen in Gebieten von rascher AMP-Verwertung.
  4. Verwendung nach einem der vorhergehenden Ansprüche, worin die mit vermindertem Blutdruck einhergehen Erkrankungen solche des Herzens sind.
  5. Verwendung nach einem der vorhergehenden Ansprüche, worin die Herzerkrankung Angina ist.
  6. Verwendung von AICA-Ribosid zur Herstellung eines Arzneimittels zur Verwendung als Vasodilator.
  7. Verwendung von AICA-Ribosid nach einem der vorhergehenden Ansprüche als lokaler Vasodilator.
  8. Verwendung nach einem der vorhergehenden Ansprüche gegen myokardiale Arrhythmie.
  9. Verwendung nach einem der vorhergehenden Ansprüche 1 bis 3 gegen Herzinfarkt.
  10. Verwendung nach Anspruch 1 gegen vorübergehende ischämische Anfälle.
  11. Verwendung nach Anspruch 1 gegen myokardiale Ischämie.
  12. Verwendung nach Anspruch 1 gegen koronaren Arterienverschluß.
  13. Verwendung nach einem der vorhergehenden Ansprüche, worin AICA-Ribosid oral, intramuskulär, topisch oder durch Inhalation verabreicht wird.
  14. Verwendung nach einem der vorhergehenden Ansprüche, worin AICA-Ribosid intravenös verabreicht wird.
EP86902696A 1986-03-27 1986-04-08 AICA riboside zur prophylaktischen Behandlung von Krankheiten mit einer verminderten Durchblutung. Expired - Lifetime EP0262125B1 (de)

Priority Applications (1)

Application Number Priority Date Filing Date Title
EP94107553A EP0623348A1 (de) 1986-03-27 1986-04-08 Die Verwendung von AICA Riboside und Ribavirin zur Herstellung eines Arzneimittels für die Behandlung von Allergien

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US84562786A 1986-03-27 1986-03-27
US845627 1986-03-27
PCT/US1986/000736 WO1987005807A1 (en) 1986-03-27 1986-04-08 A method of increasing adenosine excretion

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EP94107553.3 Division-Into 1986-04-08

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EP0262125A1 EP0262125A1 (de) 1988-04-06
EP0262125A4 EP0262125A4 (de) 1989-07-26
EP0262125B1 true EP0262125B1 (de) 1996-03-27

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EP86902696A Expired - Lifetime EP0262125B1 (de) 1986-03-27 1986-04-08 AICA riboside zur prophylaktischen Behandlung von Krankheiten mit einer verminderten Durchblutung.
EP94107553A Withdrawn EP0623348A1 (de) 1986-03-27 1986-04-08 Die Verwendung von AICA Riboside und Ribavirin zur Herstellung eines Arzneimittels für die Behandlung von Allergien

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EP94107553A Withdrawn EP0623348A1 (de) 1986-03-27 1986-04-08 Die Verwendung von AICA Riboside und Ribavirin zur Herstellung eines Arzneimittels für die Behandlung von Allergien

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EP (2) EP0262125B1 (de)
JP (1) JP2509202B2 (de)
AT (1) ATE135914T1 (de)
AU (3) AU5668886A (de)
BR (1) BR8607124A (de)
DE (1) DE3650505T2 (de)
DK (1) DK175693B1 (de)
FI (1) FI875245A (de)
WO (1) WO1987005807A1 (de)

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US4912092A (en) * 1986-03-27 1990-03-27 The Regents Of The University Of California Methods for increasing extracellular adenosine and for stabilizing mast cells
US5132291A (en) * 1989-01-24 1992-07-21 Gensia Pharmaceuticals, Inc. Antivirals and methods for increasing the antiviral activity of azt
IL93164A0 (en) * 1989-01-24 1990-11-05 Gensia Pharma Purine nucleosides and their medical use
IL103294A0 (en) * 1991-09-30 1993-05-13 Gensia Pharma Pharmaceutical compositions for preventing tissue damage associated with decreased blood flow
US5366960A (en) * 1993-08-26 1994-11-22 Warner-Lambert Company Method of treating cerebral and cardiovascular disorders employing [R]3-(2-deoxy-β-D-erythro-pentofuranosyl)-3,6,7,8-tetrahydroimidaz 0-[4,5-d][1,3]diazepin-8-ol
EP1174141A3 (de) * 1996-01-23 2003-04-23 ICN Pharmaceuticals, Inc. Regulierung der TH1/TH2 Cytokinexpression durch Ribavirin and Ribavirinanaloge in activierten T-Lymphocyten
US6680292B1 (en) 1998-11-20 2004-01-20 The Salk Institute For Biological Studies Pharmaceutical composition comprising ribavirin and growth factors and methods of use
AU2026900A (en) * 1998-11-20 2000-06-13 Salk Institute For Biological Studies, The Neuron stimulation by ribavirin, and analogs thereof
CA2357735A1 (en) * 1999-01-29 2000-08-03 Icn Pharmaceuticals, Inc. Modulation of immune response by ribavirin
SK8612002A3 (en) * 1999-12-23 2003-03-04 Ribapharm Inc Compositions and methods for L-nucleosides, L-nucleotides, and their analogs
EP2594273A1 (de) 2005-03-28 2013-05-22 Pericor Therapeutics, Inc. Verfahren, Zusammensetzungen und Formulierungen zur Prävention BZW. reduktion von Nebenwirkungen bei einem Patienten
AU2006339963B2 (en) * 2006-03-14 2010-02-25 Wholesome Biopharm Pty Ltd Method and composition for treating allergic diseases
EP2349284B1 (de) 2008-10-03 2016-11-23 Pericor Therapeutics, Inc. Behandlung von akuter decompensierter herzinsuffizienz

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Title
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FI875245A0 (fi) 1987-11-27
JPS63503061A (ja) 1988-11-10
DE3650505T2 (de) 1996-09-19
EP0262125A4 (de) 1989-07-26
AU672243B2 (en) 1996-09-26
BR8607124A (pt) 1988-04-05
AU5668886A (en) 1987-10-20
AU5198693A (en) 1994-02-03
ATE135914T1 (de) 1996-04-15
EP0262125A1 (de) 1988-04-06
DE3650505D1 (de) 1996-05-02
AU6006090A (en) 1990-11-08
FI875245A (fi) 1987-11-27
DK621487D0 (da) 1987-11-26
JP2509202B2 (ja) 1996-06-19
DK175693B1 (da) 2005-01-24
EP0623348A1 (de) 1994-11-09
WO1987005807A1 (en) 1987-10-08
DK621487A (da) 1988-01-26

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